NM_000430.4:c.37C>G

Variant names:

• chr17-2665376-C-G
• rs587784262
• NM_000430.4:c.37C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000430.4(PAFAH1B1):​c.37C>G​(p.Arg13Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,589,808 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R13Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAFAH1B1 NM_000430.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 2 publications found

Genes affected

PAFAH1B1 (HGNC:8574): (platelet activating factor acetylhydrolase 1b regulatory subunit 1) This locus was identified as encoding a gene that when mutated or lost caused the lissencephaly associated with Miller-Dieker lissencephaly syndrome. This gene encodes the non-catalytic alpha subunit of the intracellular Ib isoform of platelet-activating factor acteylhydrolase, a heterotrimeric enzyme that specifically catalyzes the removal of the acetyl group at the SN-2 position of platelet-activating factor (identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). Two other isoforms of intracellular platelet-activating factor acetylhydrolase exist: one composed of multiple subunits, the other, a single subunit. In addition, a single-subunit isoform of this enzyme is found in serum. [provided by RefSeq, Apr 2009]

PAFAH1B1 Gene-Disease associations (from GenCC):

• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000430.4
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000430.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	NM_000430.4	MANE Select	c.37C>G	p.Arg13Gly	missense	Exon 3 of 11	NP_000421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	ENST00000397195.10	TSL:1 MANE Select	c.37C>G	p.Arg13Gly	missense	Exon 3 of 11	ENSP00000380378.4
	PAFAH1B1	ENST00000572915.6	TSL:1	n.273-1616C>G		intron	N/A
	PAFAH1B1	ENST00000713690.1		c.-159C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	ENSP00000518994.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151866 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437942 Hom.: 0 Cov.: 27 AF XY: 0.00000279 AC XY: 2 AN XY: 716822

African (AFR) AF: 0.00 AC: 0 AN: 32942

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4202

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1092422

Other (OTH) AF: 0.00 AC: 0 AN: 59366

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151866 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74136

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.49
Sift	Benign	0.071	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.86
MutPred		0.52		Gain of sheet (P = 0.0016)
MVP		0.93
MPC		1.4
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.58
gMVP		0.94
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587784262; hg19: chr17-2568670;